Pilots are trained to guard against vertigo: a sudden loss of the sense of vertical direction that renders them unable to tell “up” from “down” and sometimes even leads to crashes. Coming up out of a subway station can produce similar confusion: For a few moments, you are unsure which way to go, until regaining your sense of direction. In both cases, the disorientation is thought to be caused by a temporary malfunction of a brain circuit that operates as a three-dimensional (3D) compass.
Weizmann Institute scientists have now for the first time demonstrated the existence of such a 3D compass in the mammalian brain. The study was performed by graduate student Arseny Finkelstein in the laboratory of
Prof. Nachum Ulanovsky of the Neurobiology Department, together with Dr. Dori Derdikman, Dr. Alon Rubin, Jakob N. Foerster and Dr. Liora Las. As reported in
Nature on December 3, the researchers have shown that the brains of bats contain
neurons that sense which way the bat’s head is pointed and could therefore support the animal’s navigation in 3D space.
Navigation relies on spatial memory: past experience of different locations. This memory is formed primarily in a deep-seated brain structure called the hippocampal formation. In mammals, three types of brain cells, located in different areas of the hippocampal formation, form key components of the navigation system: “place” and “grid” cells, which work like a GPS, allowing animals to keep track of their position; and “head-direction” cells, which respond whenever the animal’s head points in a specific direction, acting like a compass. Much research has been conducted on place and grid cells, whose discoverers were awarded the 2014 Nobel Prize in Physiology or Medicine, but until recently, head-direction cells have been studied only in two-dimensional (2D) settings, in rats, and very little was known about the encoding of 3D head direction in the brain.
To study the functioning of head-direction cells in three dimensions, Weizmann Institute scientists developed a tracking apparatus that allowed them to video-monitor all the three angles of head rotation – in flight terminology, yaw, pitch and roll – and to observe the movements of freely-behaving Egyptian fruit bats. At the same time, the bats’ neuronal activity was monitored via implanted microelectrodes. Recordings made with the help of these microelectrodes revealed that in a specific sub-region of the hippocampal formation, neurons are tuned to a particular 3D angle of the head: Certain neurons became activated only when the animal’s head was pointed at that 3D angle.
The study also revealed for the first time how the brain computes a sense of the vertical direction, integrating it with the horizontal. It turns out that in the neural compass, these directions are computed separately, at different levels of complexity: The scientists found that head-direction cells in one region of the hippocampal formation became activated in response to the bat’s orientation relative to the horizontal surface, that is, facilitating the animal’s orientation in two dimensions, whereas cells responding to the vertical component of the bat’s movement – that is, a 3D orientation – were located in another region. The researchers believe that the 2D head-direction cells could serve for locomotion along surfaces, as happens in humans when driving a car, whereas the 3D cells could be important for complex maneuvers in space, such as climbing tree branches or, in the case of humans, moving through multi-story buildings or piloting an aircraft.
By further experimenting on inverted bats, those hanging head-down, the scientists were able to clarify how exactly the head-direction signals are computed in the bat brain. It turned out that these computations are performed in a way that can be described by an exceptionally efficient system of mathematical coordinates (the technical term is “toroidal”). Thanks to this computational approach used by their brain, the bats can efficiently orient themselves in space whether they are moving head up or down.
This research supports the idea that head-direction cells in the hippocampal formation serve as a 3D neural compass. Though the study was conducted in bats, the scientists believe their findings should also apply to non-flying mammals, including squirrels and monkeys that jump between tree branches, as well as humans. “Now this blueprint can be applied to other species that experience 3D in a more limited sense,” Prof. May-Britt Moser, one of the 2014 Nobel laureates, writes in the “News and Views” opinion piece that accompanies the Weizmann study in Nature.
Prof. Ulanovsky's research is supported by the Rowland and Sylvia Schaefer Family Foundation; Mike and Valeria Rosenbloom through the Mike Rosenbloom Foundation; the Irving B. Harris Foundation; Mr. and Mrs. Steven Harowitz, San Francisco, CA; and the European Research Council.
.jpg "Immunofluorescence microscope image of the choroid plexus. Epithelial cells are in green and chemokine proteins (CXCL10) are in red")
_2.jpg "Measuring the response to novelty: A mouse repeatedly touches the object and pulls away (nose and whisker contacts are color-coded; d is the distance of the snout from the object)")
When Genes Conspire to Cause Disease
Such disease-encoding genes are generally identified in so-called genome-wide association studies. The idea is to compare genomic sequences of thousands of subjects – patients as well as healthy people – and search for tiny differences of just one or two “letters” in the genetic sequences that make up the genes. If certain variations appear more frequently in those with a disease such as schizophrenia than in the healthy population, one can start asking whether the change in that particular letter is connected to the disease.
But with hundreds of somewhat feeble candidates, the data dissolve into “noise.” There is little way to tell if the switched letter is an alternate spelling or punctuation, or whether it will be like substituting “pear” for “peach” in a recipe – a slight but possibly significant alteration to the final dish. To further complicate things, many of the substituted letters in the genomes of people with schizophrenia show up in so-called non-coding regions – those that do not contain instructions for making proteins but, rather, regulate such things as protein levels. These sequences are not only less well studied and harder to identify than the ones in coding regions; their functions are difficult to observe in standard lab tests.
Now the team had two very different sets of information – genes identified in the broad, genome-wide studies and the mRNA levels from the brain database – giving them a sort of “filter” that enabled them to identify the genetic sequences whose slight misspelling was not only associated with the disease but also exhibited interesting patterns of expression in the brain.
The team then began to analyze their narrowed-down list of genes: The approach Domany has developed over the years looks for the actions of groups of genes, rather than searching for the effects of a single gene, and this strategy worked well for the schizophrenia data. Using algorithms he and his team have developed to first identify paired correlations and from these, clusters, they ultimately identified a collection of around 19 genes that clearly stood out from the noise.
Now the question was: What does this group of genes do? That question is far from simple: there are hundreds of ways that these genes could interact and thousands of possible effects of their actions. Further computational analysis of the data revealed that the cluster of genes they had identified is associated with the functioning of the cells’ calcium channels. Nerve cells rely on these channels in their membranes to regulate the uptake of calcium ions, which excite the cells to action. Additional tests using information from the genome-wide studies and databases of protein interaction analyses supported their results.
Hertzberg says that these findings give strong backing to the idea that calcium regulation plays a central role in schizophrenia, and adds that the genetic interactions they have revealed might present useful targets for drugs. Domany points out that the next step is to understand exactly how the regulation of calcium signaling goes awry in the disease – a step that will require much more research. But the scientists are hopeful that their results, in addition to pointing to a fruitful approach to understanding how genes contribute to neuropsychological disease might, in the future, lead to both better diagnostics and possible treatments for schizophrenia.
Prof. Eytan Domany’s research is supported by the Leir Charitable Foundations; and the Louis and Fannie Tolz Collaborative Research Project. Prof. Domany is the incumbent of the Henry J. Leir Professorial Chair.